PIK3CA Mutations Matter in HER2-Positive Breast Cancer

While preclinical studies indicate that PIK3CA mutations result in resistance to the two HER2-targeted therapies trastuzumab and lapatinib, two recently published studies suggest that this mutation cannot be used as a predictive biomarker to guide therapy.

The first study found that PIK3CA mutations are associated with a decreased benefit to neoadjuvant HER2-directed therapies. The second study showed that PIK3CA mutations did not affect outcomes for HER2-positive patients receiving adjuvant trastuzumab treatment.

Preclinical studies using HER2-positive cell lines have previously shown that an additional mutation in PIK3CA, the alpha-catalytic subunit of PI3K, results in downstream constitutive signaling, making breast tumor cells that harbor both aberrations resistant to trastuzumab and lapatinib. PIK3CA is among the most commonly mutated oncogene in breast cancer and is present in about one-fourth of all HER2-positive breast cancers. Because of this prevalence and the effect of PI3K pathway activation on HER2 therapy, clinicians have posited that PIK3CA mutations may serve as predictive biomarkers, both preventing ineffectual therapy in some patients and guiding appropriate treatment choices.

In the neoadjuvant analysis, Ian J. Majewski, MD, of the Netherlands Cancer Institute in Amsterdam, and colleagues, analyzed baseline tissue biopsies from HER2-positive early breast cancer patients enrolled in the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial. The results of this analysis were published in the Journal of Clinical Oncology.

They found that PIK3CA mutations were identified in 23% of HER2-positive breast tumors. These mutations were associated with poorer outcomes in all three of the trial’s treatment arms-trastuzumab, lapatinib, and the combination of both. While there were numerical differences in pathologic complete response (pCR) between the PIK3CA-harboring patients and the wild-type PIK3CA patients in each treatment arm, only the difference between the two cohorts in the combination therapy arm was statistically significant.

The women with wild-type PIK3CA tumors treated with the combination therapy had a 53.1% pCR rate compared with 28.6% for the women whose tumors harbored a PIK3CA activating mutation (P = .012). But, PIK3CA mutation status did not affect overall survival outcomes (P = .014).

In the adjuvant analysis, published in the Journal of Clinical Oncology, Katherine L. Pogue-Geile, PhD, of the division of pathology at the National Surgical Adjuvant Breast and Bowel Project (NSABP) in Pittsburgh, and colleagues found that PIK3CA mutations are not useful as predictive biomarkers for adjuvant trastuzumab therapy. The authors analyzed data from 671 women with HER2-positive disease who took part in the NSABP B-31 trial.

A total of 166 women (24.7%) had tumors with a mutation in PIK3CA. There was no difference in outcome between the women who did and did not harbor a PIK3CA mutation (P = .64). “These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting,” concluded the authors.

In an accompanying editorial, David W. Cescon, MD, and Philippe L. Bedard, MD, of Princess Margaret Cancer Centre in Toronto, proposed that the differing results of these two studies suggest that the way the PIK3CA mutation interacts with HER2-targeted therapy may be different within the primary tumor and within micrometastases. The discrepancy between the adjuvant setting results and the in vitro data may be at least partly explained by the ability of trastuzumab to mediate antibody-dependent cellular cytotoxicity, according to the editorial authors.

Whether PIK3CA mutation status could be a useful biomarker to predict response to treatment needs to be tested in clinical trials, added Cescon and Bedard.